Abstract Human Papillomavirus (HPV) is a cause in 5% of the estimated 14+ million new cases of cancer annually. HPV-associated cancers most commonly include female cervical, oropharyngeal, and anal cancers, with about 70,000 new cases and 14,000 deaths in the U.S. alone annually. While preventive vaccination is available, current vaccines are antibody-based and do not slow or prevent the development of cancer from established HPV infection, and the burden of cancer from HPV is not expected to decline for decades worldwide. The need for noninvasive treatments is urgent. Cellular immunity, particular Th1 phenotype CD8+ T lymphocytes (CTLs) are critical for clearing viral infections by recognizing and killing infected cells. CTLs are linked to the Major Histocompatibility Class I (MHC-I) pathway of processed antigens from cell cytoplasm. Usually this compartment is accessed by live viruses, and not by killed viruses (like the existing HPV vaccines) or proteins. For this project, we will harness a novel vector, the endogenous human ?vault? protein nanoparticle, as a therapeutic vaccine to interrupt and/or treat HPV infection and HPV-associated pre-cancer. We have generated several prototype vaults containing different HPV antigens and our preliminary data demonstrates that our prototype HPV-vault vaccines induce striking frequencies of both CD4+ and CD8+ T cells targeting the delivered antigens. Vault HPV vaccines activated between 15 - 45% of total CD8+ T cells and 70 - 80% of total CD4+ T-cells. Preliminary studies on genital tract (GT) T lymphocytes post vaccination also indicated robust activation of CD8+ and CD4+ T cells. This proposal will establish a candidate a CTL- generating effective HPV vaccine.